Procee for the racemisation of 1-benzyl-4-(4-fluorophenyl)-3-hydroxymethyl-1,2-3,6-tetrahydropyridine to be used as intermediate in the synthesis of paroxetine

ABSTRACT

A process for the racemisation of enantiomerically enriched 1-benzyl-4-(4-fluorophenyl)-3-hydroxymethyl-1,2,3,6-tetrahydropyridine which is a useful intermediate in the preparation of paroxetine. Formula (A) means that the compound (I) has an enantiomeric excess of one enantiomer over the other enantiomer. R1 and R2 are defined as in claim 1.

[0001] This invention relates to a process for the racemisation ofenatiomerically enriched1-benzyl-4-(4-fluorophenyl)-3-hydroxy-methyl-1,2,3,6-tetrahydropyridinewhich is a useful intermediate in the preparation of paroxetine.

[0002] U.S. Pat. No. 4,007,196 discloses compounds which possessanti-depressant activity. One particular compound disclosed in thispatent is known as paroxetine and has the structure A below:

[0003] This compound has been found to be especially useful in thetreatment of depression and several processes have been described toprepare this important compound. WO 96/36636 (which is incorporatedherein by reference) discloses one such process. WO 98/52920 (which isincorporated herein by reference) discloses a process for preparing auseful intermediate in the preparation of paroxetine.

[0004] WO 98/01424 (which is incorporated herein by reference) disclosesa process for the preparation of racemictrans-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)piperidine in which4-(4-fluoro-phenyl)-N-benzyl-1,2,5,6-tetrahydropyridine is reacted withformaldehyde in acidic medium via the Prins reaction to give the desiredproduct. One of the optional next stages for the process is theresolution of this compound with an optically active acid, preferablydibenzoyltartaric acid ordi-p-toluyl-tartaric acid, to give theindividual enantiomers oftrans-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)piperidine. Clearlythis process is wasteful in that 50% of the material is then discardedas only one enantiomer, the (+)-enantiomer, is further processed to giveparoxetine. It would be desirable to be able to racemise the unwantedenantiomer and to then resolve the racemic mixture to produce more ofthe desired enantiomer. However, many attempts by the present applicantsto find a satisfactory racemisation process ended in failure.

[0005] Surprisingly an efficient process for carrying out thisracemisation has now been found.

[0006] The present invention provides a process for the racemisation ofa compound of formula I comprising the steps of

[0007] a) reacting an enantiomerically enriched compound of formula I

[0008] in which R₁ represents an amine protecting group, with a compoundof formula II

R₂X  II

[0009] in which R₂ represents a group of formula R₃SO_(s)—in which R₃represents optionally substituted phenyl, a C₁₋₆alkyl group or atrifluoromethyl group and X represents halo to give a compound offormula III

[0010] in which i) R₂ represents a group of formula R₃SO₂—in which R₃represents optionally substituted phenyl, a C₁₋₆alkyl group or atrifluoromethyl group,

[0011] b) reacting the compound of formula III with a compound offormula IV

[0012] in which M represents an alkali metal and R represents H, aC₁₋₆alkyl group, optionally substituted phenyl or an (optionallysubstituted phenyl)hydroxyC₁₋₆alkyl group to give a substantiallyracemic compound of formula V

[0013] in which R₁ and R are as previously defined; and

[0014] c) reacting the compound of formula V with a hydrolysing agent togive a substantially racemic compound of formula I.

[0015] It will be appreciated by those skilled in the art that thecompounds of formula III may also be prepared by reacting a compound offormula I with an halogenating agent to give a compound of formula Ia

[0016] in which Y is halo. The compound of formula Ia may then bereacted with a salt of formula MOR₂ in which R₂ is as previously definedto give a compound of formula III. This alternative process also formspart of the present invention.

[0017] Suitably halogenating agents include hydrogen bromide, hydrogenchloride, oxalyl chloride, phosphorus pentachloride, phosphorustrichloride, phosphorus pentabromide, phosphorus tribromide, bromine,phosphorus oxychloride, phosphorus oxybromide, thionyl chloride, thionylbromide, a mixture of carbon tetrachloride and triphenylphosphine, amixture of tetrabromomethane and triphenyl-phosphine, N-bromosuccinimideand N-chlorosuccinimide. Preferably the halogenating agent is thionylchloride or thionyl bromide.

[0018] Whilst not bound by theory, it is believed that the mechanism ofthe above racemisation process involves an intermediate salt which is acompound of formula IIIa

[0019] in which R₁ is as previously and R₂ ⁻ is an anion of formulaR₃SO₂ ⁻. The compound of formula IIIa in which R₂ ⁻ represents the anion⁻OSO₂CF₃ and R₁ represents benzyl has been isolated from the reactionmixture and identified. In addition the product of formula IIIa where R₂⁻ represents ⁻OSO₂-Ph has been identified in the reaction solution bynuclear magnetic resonance spectroscopy.

[0020] In a preferred aspect the present invention provides a processfor the racemisation of a compound of formula I comprising the steps of

[0021] a) reacting an enantiomerically enriched compound of formula I

[0022] in which R₁ represents an amine protecting group, with a compoundof formula II

R₂X  II

[0023] in which R₂ represents a group of formula R₃SO₂—in which R₃represents optionally substituted phenyl, a C₁₋₆alkyl group or atrifluoromethyl group and X represents halo to give a compound offormula III

[0024] in which i) R₂ represents a group of formula R₃SO₂—in which R₃represents optionally substituted phenyl, a C₁₋₆alkyl group or atrifluoromethyl group, wherein the compound of formula III is inequilibrium with a compound of formula IIIa

[0025] in which R₁ represents an amine protecting group and R₂—is ananion of R₂

[0026] b) reacting the compound of formula IIIa with a compound offormula IV

[0027] in which M represents an alkali metal and R represents H, aC₁₋₆alkyl group, optionally substituted phenyl or an (optionallysubstituted phenyl)hydroxyC₁₋₆alkyl group to give a substantiallyracemic compound of formula V

[0028] in which R₁ and R are as previously defined; and

[0029] c) reacting the compound of formula V with a hydrolysing agent togive a substantially racemic compound of formula I.

[0030] In a further aspect the present invention provides compounds offormula IIIa

[0031] in which R₁ represents an amine protecting group and R₂ is apreviously stated. Preferably R₁ represents benzyl or a C₁₋₆-alkylgroup. More preferably R₁ represents benzyl, methyl or ethyl. Mostpreferably R₁ represents benzyl. Preferably R₂ ⁻ is a benzene-sulphonateanion, a methanesulphonate anion or a trifluoro-methanesulphonate anion.

[0032] Preferably the amino protecting group is one which is inert toreduction by a metal hydride. More preferably the amine protecting groupis selected from a) allyl, b) benzhydryl, c) methoxymethyl, d)benzyloxymethyl, e) tetrahydropyranyl, f) an optionally substitutedbenzyl group, g) di(p-methoxy-phenyl)methyl, h) triphenylmethyl, i)(p-methoxyphenyl)diphenyl-methyl, j) diphenyl-4-pyridylmethyl, k) aC₁₋₆alkyl group, for example methyl or ethyl, 1) a trifluoro C₁₋₄alkylgroup, m) an alkynyl group or n) p-methoxybenzyl. Most preferably theamine protecting group is a benzyl group which is optionally substitutedon the phenyl ring by one or more of the following groups: a C₁₋₄alkylgroup, a C₁₋₄alkoxy group, halo or nitro. Especially preferably R₁represents benzyl.

[0033] The term optionally substituted phenyl means phenyl substitutedby one or more of the following: a) a C₁₋₆alkyl group, b) nitro or c)halo.

[0034] The term enantiomerically enriched should be understood to meanthat the compound of formula I has an enantiomeric excess of oneenantiomer over the other enantiomer in the range of 1 to 100%,preferably an enantiomeric excess in the range of 50 to 100%, and morepreferably an enantiomeric excess in the range of 70 to 100%.

[0035] Suitably either enantiomer may predominate in theenantiomerically enriched compound. Preferably the predominantenantiomer is the (+) enantiomer. More preferably the predominantenantiomer is the (−)enantiomer.

[0036] The term substantially racemic means that there is anenantiomeric excess of less than 20% preferably less than 10% and mostpreferably less than 5%.

[0037] Preferably R₃ represents methyl or phenyl optionally substitutedby a methyl group, a nitro group or halo. More preferably R₃ representsmethyl, 4-tolyl, 4-nitrophenyl, or 4-bromophenyl.

[0038] Suitably the hydrolysing agent includes a basic or acidichydrolysing agent. Preferred basic hydrolysing agents include aqueoussodium hydroxide, aqueous ammonia, aqueous potassium carbonate, aqueouspotassium bicarbonate, aqueous sodium bicarbonate, aqueous sodiumcarbonate, potassium hydroxide, aqueous potassium hydroxide and aqueouslithium hydroxide. Preferred acidic hydrolysing agents includehydrochlorid acid, hydrobromic acid and sulphuric acid. Most preferablythe hydrolysing agent is aqueous hydrochloric acid or aqueous sodiumhydroxide solution.

[0039] In another aspect the present invention provides novel compoundsof formula III and V in which RI and R are as previously defined whichare useful as intermediates in the preparation of paroxetine. PreferablyR₁ is benzyl. Preferably R is methyl. Preferably M is potassium.

[0040] In yet another aspect the present invention provides a processfor the preparation of paroxetine from a compound of formula I accordingto the methods described in WO 96/36636, and WO 98/01424 characterisedin that the compound of formula I was prepared by racemisation of anenantiomerically enriched compound of formula I by the process of thepresent invention. The paroxetine may be obtained as the hydrochloridesalt as the anhydrous form or the hemihydrate or other solvate. Theprocess of the present invention may also be used in conjunction withthe process described in WO 98/52920 to prepare an intermediate whichmay be further processed as described below to produce paroxetine. Thesecombination processes also form part of the present invention.

[0041] The process of the present invention is advantageous because itprovides a pure precursor to paroxetine. Paroxetine may be obtained in apure form from compounds of formula I by a) conversion of the hydroxygroup into a leaving group, for example halo or tosyloxy, b) reactionwith sesamol or a salt thereof, c) removal of the protecting group R₁ isbenzyl and optionally d) salt formation, for example the hydrochloridesalt as the anhydrous form or the hemihydrate.

[0042] The invention is illustrated by the following Examples which aregiven by way of example only. The final product of each of theseExamples was characterised by one or more of the following procedures:gas-liquid chromatography: high performance liquid spectroscopy andinfrared spectroscopy.

EXAMPLES Example 4

[0043] Triethylamine (3.2 ml) was added to a solution of (+)-benzyl-3-hydroxymethyl-44-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (5.65 g)in toluene (44.35 g) and the mixture was stirred at ambient temperature.The solution was cooled to ° C. in an ice/water bath and themethanesulphonyl chloride (1.6 ml) was added dropwise over a minute. Thetemperature rose to 11° C. over 5 minutes and then dropped to 5° C. over5 minutes. The mixture was stirred at 0 - 5° C. for 75 minutes. Themixture was allowed to warm to 10° C. and water (10 ml) was added. Themixture was stirred for 5 minutes and then the organic layer wasseparated, washed with water (20 ml), and then dried, filtered andevaporated to (+)-1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-3-methyl methanesulphonate as an oil whichsolidified on standing. [α]_(p)21.5° C. =+78.2 ±1.4) concentration1.0735 g per 100 ml of chloroform.

Example 5

[0044] Potassium acetate (1.23 g) and 18-crown-6 (0.3 g) were added to astirred solution of(+)-1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-3-methylmethanesulphonate (4.27 g) in acetonitrile (50 ml) with stirring. Themixture was stirred at ambient temperature for 1.5 hours and then boiledunder reflux with stirring for 5 hours. The mixture was allowed to standat ambient temperature for 64 hours and then boiling under reflux wascontinued for a further 5 hours. The mixture was cooled to ambienttemperature and then ethyl acetate (50 ml) and water (50 ml) were added.The mixture was stirred for approximately 5 minutes and then brine (20ml) was added to the mixture followed by dry ethyl acetate (10 ml). Theorganic layer was separated, washed with brine (50 ml), dried, filteredand evaporated to give(+,-)-1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-3-methylacetate.

Example 6

[0045] Aqueous sodium hydroxide solution (9.6 ml of a 4M solution) wasadded to a solution of(+,-)-1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-3-methylacetate (2.6 g) in industrial methylated spirits (26 ml) with stirring.The mixture was boiled under reflux for 1.5 hours. The mixture wasevaporated under reduced pressure and then toluene (40 ml) and water (20ml) were added. The organic layer was removed, washed with water, andthen dried, filtered and evaporated to give(+,-)-l-benzyl-3-hydroxy-methyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(ee 16.3%).

Example 7

[0046] A solution of(−)-enriched)-1-benzyl-3-hydroxymethyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine(19.8 g) in toluene (100 g) which had been previously dried byazeotropic distillation, was stirred at ambient temperature whilsttriehylamine (13.9 ml) and benzenesulphonyl chloride (9.9 ml) wereadded. The mixture was stirred at ambient temperature for 64 hours.Water (64 ml) was added and the mixture was stirred for approximately 15minutes. The organic layer was separated off, washed with water and asample (10 ml) was removed for analysis. The remaining toluene solutionwas boiled under reflux with azeotropic removal of the water using aDean & Stark apparatus for approximately 15 minutes. The mixture wascooled to ambient temperature and potassium acetate (7.18 g) andpropan-2-ol (97.2 ml) were added. The mixture was boiled under refluxfor 19 hours, then cooled to 45° C. and an aqueous solution of sodiumhydroxide (66.6 ml of a 4M solution) and water (33 ml) were added. Theresulting 2-phase mixture was boiled and stirred under reflux for 1.75hours. Solvent (60 ml) was removed by distillation and the mixture wasallowed to cool to ambient temperature. The organic layer was separated,washed with water then evaporated under reduced pressure to give (+,−)-1-benzyl--hydroxymethyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridineas an oil (ee 5.4%)

Example 8

[0047] Triethylamine (1.39 ml) and benzenesulphonyl chloride (9.9 ml)were added to a solution of(−)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(19.8 g) made up to 100 g with toluene, with stirring under nitrogen.The mixture was stirred at ambient temperature for 72 hours. Water (64ml) was added and the mixture was stirred for 15 minutes. The organiclayer was separated, washed with water and a small sample of thesolution (5 ml) was removed. The remaining toluene solution was stirredwhile potassium acetate (7.18 g) and 4-methyl-2-pentanol (71 ml) wereadded. The mixture was then boiled and stirred under reflux with removalof water via a Dean & Stark apparatus for 5.5 hours. The mixture wasallowed to cool to ambient temperature and stood at this temperature for18 hours. Water (64 ml) was added and the mixture was stirred for 5minutes. The aqueous layer was separated off. The organic layer wasreturned to the reaction flask and stirred while water (51.2 ml)followed by concentrated hydrochloric acid (28.6 ml) were added. Thismixture was boiled under reflux for 1.5 hours. The reaction mixture wascooled to around 40° C. and the concentrated aqueous ammonia (22.1 ml)was added dropwise keeping the temperature below 45° C. Moreconcentrated aqueous ammonia solution (6 ml) was added to give a finalpH of 8 -9. The reaction mixture was stirred for around 15 minutes andthen cooled to ambient temperature. The organic layer was separated,washed with water, dried and evaporated to give(+,−)-1-benzyl-3-hydroxymethyl-4-(4-fluoro-pheynl)-1,2,3,6-tetrahydropyridine(ee 4.47%).

Example 9

[0048] Triethylamine (12.9 ml) was added to a solution of(−)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(25.0 g) made up to 137 g with toluene, with stirring under nitrogen.The solution was cooled to 5° C. in an ice/water bath andmethanesulphonyl chloride (6.6 ml) was added dropwise over 20 minuteskeeping the temperature below 10° C. The mixture was stirred at 0 - 10°C. for 45 minutes. 4-Methyl-2-pentanol (6.5 ml) was added and themixture stirred for a further 15 minutes. The mixture was allowed towarm to 20° C. and water (40 ml) was added. The mixture was stirred for15 minutes and then the organic layer was separated, and washed withwater (40 ml). The remaining toluene solution was stirred whilepotassium acetate (9.5 g) and 4-methyl-2-pentanol (19.5 ml) were added.The mixture was then boiled and stirred under reflux with removal ofwater via a Dean & Stark apparatus for 15 to 20 hours. The mixture wasallowed to cool to 50° C. Water (40 ml) was added and the mixture wasstirred for 15 minutes. The aqueous layer was separated off. The organiclayer was returned to the reaction flask and stirred while water (12.8ml) followed by concentrated hydrochloric acid (10.2 ml) were added.This mixture was boiled under reflux for 3 hours. The reaction mixturewas cooled to around 40° C. and then concentrated aqueous ammonia (23ml) was added dropwise keeping the temperature below 45° C. to give afinal pH of 8-9. The reaction mixture was stirred for around 15 minutesand then cooled to ambient temperature. The organic layer was separated,washed with water (2×40 ml) and evaporated to give(+,−)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(ee 9.0%).

Example 10

[0049] Triethylamine (1.5 ml) was added to a solution of(+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(2.82 g) in toluene (22.18 g) and the mixture was stirred at ambienttemperature. The solution was cooled to 50C in an ice/water bath and thetrifluoromethanesulphonic anhydride (1.8 ml) was added dropwise over 5minutes. The mixture was stirred at 0° C. to room temperature for 4hours, then stood for 48 hours. Water (25 ml) was added. The mixture wasstirred for 2 minutes and then ethyl acetate and 4M-NaOH were added todissolve an insoluble oil. The organic layer was separated, washed withwater (25 ml), and then dried, filtered and evaporated to give1-benzyl-4-(4-fluorophenyl)-l-azoniabicyclo[3.1.1]hept-3-enetrifluoro-methanesulphonate as an oil The oil was triturated with 60-80°C. petrol to give a solid.

Example 11

[0050] Potassium acetate (0.14 g) was added to a stirred solution of1-benzyl-4-(4-fluorophenyl)-l-azoniabicyclo[3.1.1]hept-3-enetrifluoromethanesulphonate (0.5 g) in toluene (2.5 ml) and propan-2-ol(2.5 ml). The mixture was then boiled and stirred under reflux for 24hours. The mixture was cooled to room temperature and toluene (10 ml)and water (5 ml) were added. The organic layer was separated, dried andevaporated to leave an oil. A solution of the oil in propan-2-ol (2 ml)and toluene (2 ml) was treated with 4M-NaOH (0.4 ml). The mixture wasboiled under reflux for 2 hours then cooled to room temperature. Water(5 ml) and toluene 95 ml) were added. The organic layer was separated,washed with water (2×5 ml) and evaporated to give(+,−)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(ee 5.48%).

1. A process for the racemisation of a compound of formula I comprisingthe steps of a) reacting an enantiomerically enriched compound offormula I

in which R₁ represents an amine protecting group, with a compound offormula II R₂X  II in which R₂ represents a group of formula R₃SO_(s)—inwhich R₃ represents optionally substituted phenyl, a C₁₋₆alkyl group ora trifluoromethyl group and X represents halo to give a compound offormula III

in which i) R₂ represents a group of formula R₃SO₂—in which R₃represents optionally substituted phenyl, a C₁₋₆alkyl group or atrifluoromethyl group, b) reacting the compound of formula III with acompound of formula IV

in which M represents an alkali metal and R represents H, a C₁₋₆alkylgroup, optionally substituted phenyl or an (optionally substitutedphenyl)hydroxyC₁₋₆alkyl group to give a substantially racemic compoundof formula V

in which R₁ and R are as previously defined; and c) reacting thecompound of formula V with a hydrolysing agent to give a substantiallyracemic compound of formula
 1. 2. A process for the racemisation of acompound of formula I comprising the steps of a) reacting anenantiomerically enriched compound of formula I

in which R₁ represents an amine protecting group, with a compound offormula II R₂X  II in which R₂ represents a group of formula R₃SO_(s)—inwhich R₃ represents optionally substituted phenyl, a C₁₋₆alkyl group ora trifluoromethyl group and X represents halo to give a compound offormula III

in which i) R₂ represents a group of formula R₃SO₂—in which R₃represents optionally substituted phenyl, a C₁₋₆alkyl group or atrifluoromethyl group, wherein the compound of formula III is inequilibrium with a compound of formula IIIa

in which R₁ represents an amine protecting group and R₂—is an anion ofR₂ b) reacting the compound of formula IIIa with a compound of formulaIV

in which M represents an alkali metal and R represents H, a C₁₋₆alkylgroup, optionally substituted phenyl or an (optionally substitutedphenyl)hydroxyC₁₋₆alkyl group to give a substantially racemic compoundof formula V

in which R₁ and R are as previously defined; and c) reacting thecompound of formula V with a hydrolysing agent to give a substantiallyracemic compound of formula
 1. 3. A process according to claim 1 inwhich the amine protecting group is selected from a) allyl, b)benzhydryl, c) methoxymethyl, d) benzyloxymethyl, e) tetrahydropyranyl,f) an optionally substituted benzyl group, g) di(p-methoxyphenyl)methyl,h) triphenylmethyl, i) (p-methoxyphenyl)diphenylmethyl, j)diphenyl-4-pyridylmethyl, k) a C₁₋₆alkyl group, for example methyl orethyl, l) a trifluoro C₁₋₄alkyl group, m) an alkynyl group or n)p-methoxybenzyl.
 4. A process according to claim 1 in which R₃represents methyl or phenyl optionally substituted by a methyl, group, anitro group or halo.
 5. A process according to claim 1 in which thehydrolysing agent is selected from one or more of the following: aqueoussodium hydroxide, aqueous ammonia, aqueous potassium carbonate, aqueouspotassium bicarbonate, aqueous sodium bicarbonate, aqueous sodiumcarbonate, potassium hydroxide, aqueous potassium hydroxide and aqueouslithium hydroxide.
 6. A compound of formula IIIa

in which R₁ represents an amine protecting group and R₂ is as previouslystated. Preferably R₁ represents benzyl or a C₁₋₆alkyl group.